The present invention relates to xcex4 receptor agonist compounds and their use in the treatment of pain. Specifically, tricyclic xcex4 receptor agonist compounds are disclosed, which have a tricyclic structure comprising a non-aromatic central ring flanked by two aromatic rings, and an optional pendant, substituted, piperazine or piperidine, together with their methods of use for the treatment of pain with reduced risk of induction of seizure in a patient.
Clozapine (CLZ, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]-diazepine) is an atypical antipsychotic or neuroleptic agent that is a dibenzodiazepine derivative with a piperazinyl side chain. It displays antipsychotic efficacy against positive and negative symptoms of schizophrenia in patients who do not respond to typical neuroleptics. It is metabolized via the hepatic microsomal enzyme system into two major metabolites: N-desmethylclozapine (DMCLZ) and clozapine N-oxide. DMCLZ has been shown to reach a plasma level of xcx9c620 nM in human patients and is a potent 5HT1C receptor antagonist.
Clozapine inhibits binding at xcex4 opioid receptors (Kobayashi, T., Ikeda, K. and Kumanishi, T. (1998) Br. J. Pharmacol. 123:421-6). Clozapine also acts as a kappa agonist and as a G-protein-activated inwardly rectifying K+ (GIRK) channel blocker. However, clozapine and other atypical antipsychotic agents frequently possess untoward side-effects, including induction of seizures. There is therefore a need, within the field of opioid receptor agonists, for compounds that are agonists of specific subtypes of opioid receptor that exhibit improved specificity and do not cause seizures.
The present invention addresses the aforementioned problems and more as will be apparent to one of skill in the art upon reading the following disclosure.
The present invention, in its broadest aspect, encompasses the use of xcex4 receptor agonist compounds for the treatment of pain, wherein the xcex4 receptor agonist compounds have a tricyclic structure comprising a non-aromatic central ring flanked by two or three aromatic rings, and an optional pendant, substituted, piperazine or piperidine.
In one embodiment, the invention therefore comprises the inducement of analgesia in a patient, where the methods comprise administering to a patient a xcex4 opioid receptor agonist of the general formula (I): 
wherein:
rings A and B are aromatic rings of 5-7 carbons that are optionally substituted with one or more substituents that can include F, Cl, Br, I, xe2x80x94NO2, xe2x80x94OH, xe2x80x94SO2, or (C1-C5)alkyl;
C is carbon, X is N, O, S or P, and Y is N or P;
[m] is an integer of 0 or 1, [a] is an integer of from 0 to 2, and the sum [m]+[a] is an integer of from 0 to 2;
[n] is an integer of 0 to 1, [b] is an integer of 0 to 3, and the sum [n]+[b] is an integer of from 1 to 3;
the sum [m]+[a]+[n]+[b] is an integer of from 1 to 3; and
one C[b] or one Y[n] has a pendant substituted or unsubstituted piperidine or piperazine ring.
Another aspect of the invention relates to methods of inducing analgesia in a patient, wherein the methods comprise administering to said patient an effective amount of a tricyclic xcex4 opioid receptor agonist of the formula (Ia): 
wherein:
X are each independently 0-4 substituents independently selected from the group consisting of F, Cl, Br, I, xe2x80x94NO2, xe2x80x94OH, xe2x80x94SO2, and (C1-C5)alkyl;
R1 is C, N, O or S;
R2 is C or N; and
R3 is xe2x80x94H or xe2x80x94CH3.
Still another aspect of the invention relates to methods of inducing analgesia in a patient, wherein the methods comprise administering to said patient an effective amount of a tricyclic xcex4 opioid receptor agonist of the formula (Ib): 
wherein:
X is F, Cl, Br, or I;
R1 is C, N, O or S; and
R3 is xe2x80x94H or xe2x80x94CH3.
Yet another aspect of the invention relates to methods of inducing analgesia in a patient, wherein the methods comprise administering to the patient an effective amount of a tricyclic xcex4 opioid receptor agonist of the formula (Ic): 
wherein R is xe2x80x94H or methyl, with xe2x80x94H being preferred.
Still another aspect of the invention relates to methods of inducing analgesia in a patient, said method comprising administering to said patient an effective amount of a compound selected from the group consisting of N-desmethylclozapine, amoxapine, cyproheptadine, and mixtures thereof.
Still another aspect of the invention relates to methods of inducing analgesia in a patient, wherein the methods comprise administering to said patient an effective amount of a tricyclic xcex4 opioid receptor agonist of the formula (II): 
wherein:
R4 and R5 are independently selected from alkyl, halo, haloalkyl, thio or alkoxy;
R6 is C, N, O or S;
R7 is C or N; and
R8 is xe2x80x94H or xe2x80x94CH3.
These and other aspects of the invention will become more apparent from the following detailed description.